CN111246903B

CN111246903B - Accelerated test method for silicone discharge in syringe

Info

Publication number: CN111246903B
Application number: CN201880067949.XA
Authority: CN
Inventors: B·F·刘易斯; B·M·麦加维
Original assignee: Eli Lilly and Co
Current assignee: Eli Lilly and Co
Priority date: 2017-10-18
Filing date: 2018-10-11
Publication date: 2022-08-16
Anticipated expiration: 2038-10-11
Also published as: AU2018352100A1; US11353436B2; JP6703648B2; ES2965706T3; CN111246903A; AU2018352100B2; WO2019079088A3; CA3079380A1; US20200225200A1; US10627377B2; JP2020505589A; WO2019079088A2; EP3697476B1; EP3697476A2; MX2020003627A; US20200016324A1

Abstract

A centrifugation method is disclosed for accelerating current empirical methods for studying silicone discharge in syringes. The siliconized syringe was placed in the centrifuge holder in a predetermined orientation. Centrifugation of the syringe was initiated at a predetermined G rate for a desired simulated time and ended after the time elapsed. The time may be a function of expected simulated time, acceleration due to gravitational effects, the square of the centrifuge rotational speed, and the distance from the center of the rotor hub to the mating point on the syringe cartridge. After the period of time, one or more injection function parameters of the injector are evaluated. A barrel securement device for maintaining one or more syringes in a predetermined orientation is also disclosed.

Description

Accelerated test method for silicone discharge in syringe

Cross Reference to Related Applications

This application claims the benefit of U.S. provisional application No.62/573,843 filed on 2017, 10, 18, incorporated herein by reference in its entirety.

Technical Field

The present disclosure relates to methods and systems for accelerated testing of silicone ejection in medical devices, and in particular syringes used in drug delivery devices.

Background

Syringes are used for the delivery of drugs. The syringe includes a cartridge extending between a flange and a shoulder leading to a needle hub. The medicament may be contained within a cartridge and dispensed by movement of a piston slidable along an inner wall of the cartridge. When stored, the syringe is placed with the needle end facing up and the flange end facing down. Silicone or other substance is placed along the inside wall of the syringe for lubrication and long term sealing. After silicidation of the injector, the injector may be stored for a long time. During this storage time, the initial distribution of silicone may change as the silicone drains from top to bottom (i.e., from the needle end to the flange end) under the force of gravity. These changes due to silicone expulsion must be understood to understand the effect of changes in silicone distribution in the hollow syringe during storage on the injection function and the changes in the level of silicone particles in the prefilled syringe once filled with the drug. Currently, only empirical methods are available for these types of evaluations, and these methods require long studies to record the effect of empty component storage and filled syringe storage over time. These studies may require a significant amount of time. For example, if an empty syringe cartridge needs to be stored for up to four years before filling and a filled syringe needs to be stored for up to two years after the maximum empty storage time has elapsed, it may take more than 6 years to study the combined effect of the maximum allowable empty and fill times of the syringe. Accordingly, there is a need to understand silicone ejection from a first principle perspective and to utilize this understanding to identify a method of accelerating research so that useful information can be created in much less than 6 years and/or to overcome one or more of these and other shortcomings of the prior art.

Disclosure of Invention

In one embodiment, a test method for accelerating silicone drain rate of a siliconized syringe is disclosed. The method comprises one or more of the following steps: a syringe including a silicone membrane is placed into a centrifuge rack of a centrifuge system in a predetermined orientation. The syringe includes a needle end and an opposing flange end. The predetermined orientation of the syringe includes the flanged end being disposed further from a central axis of the centrifuge system than the needle end or the needle end being disposed further from the central axis of the centrifuge system than the flanged end. The centrifugation of the centrifuge rack of the centrifuge system with the syringe is initiated at a predetermined G-rate for a predetermined period of time. After this period of time, the centrifugation of the centrifuge rack with syringe was completed. After the period of time, one or more injection function parameters of the injector are evaluated.

In another embodiment, a test method for accelerating silicone drain rate of a siliconized syringe is provided. The method comprises one or more of the following steps: a syringe including a silicone membrane is placed into a centrifuge rack of a centrifuge system in a predetermined orientation. The syringe includes a needle end and an opposing flange end. The predetermined orientation of the syringe includes the flanged end being disposed further from a central axis of the centrifuge system than the needle end or the needle end being disposed further from the central axis of the centrifuge system than the flanged end.

Starting the centrifugation of the centrifugation rack of the centrifuge system with syringe at a predetermined G-rate for a predetermined period of time (tfc), wherein said period of time (tfc) is expressed as:

wherein t is _fg Is the gravity drainage time, t, to be simulated _fc Is at a length r of the rotor arm _c Matching point z, syringe length L _F And g is acceleration due to gravity. After the period of time has elapsed, the centrifugation of the centrifuge rack with syringe is terminated.

In yet another embodiment, a syringe testing apparatus for a centrifuge system is disclosed. The syringe includes a cartridge having a cartridge diameter and a flanged end having a diameter greater than the cartridge diameter. The apparatus includes a body defining a plurality of cells extending between an upper end and a lower end of the body. Each unit includes a diameter sized to receive the cartridge of the syringe, but not the flange of the syringe. The bottom plate includes a plurality of recesses. Each recess is arranged in coaxial alignment with a respective cell of the body. Each recess includes a diameter sized to be larger than the diameter of the unit and a depth sized to capture the thickness of the flange of the syringe. The bottom plate includes an attachment feature for secure attachment to the lower end of the main body.

Drawings

Other embodiments of the present disclosure and features and advantages thereof will become more apparent by reference to the description herein taken in conjunction with the accompanying drawings. The components in the drawings are not necessarily to scale. Moreover, in the figures, like reference numerals designate corresponding parts throughout the different views.

FIG. 1 is a side cross-sectional view of one embodiment of a filled and assembled manual pre-filled syringe.

Fig. 2 is a cross-sectional partial detail of the wall of the syringe in fig. 1, depicting the syringe wall with a silicone membrane.

Fig. 3A depicts an exemplary centrifuge system for accelerated testing of silicone discharge in a syringe.

FIG. 3B is a top view of the centrifuge system of FIG. 3A.

Fig. 4 depicts the orientation and length of the syringe relative to the rotor arm of the centrifuge system in fig. 3.

Fig. 5 is a perspective view of the upper end of a stationary bucket for holding a plurality of syringes within the centrifuge system of fig. 3 during testing, illustrating the main body of the stationary bucket in an upright position with the base removed from the lower end of the holder body.

Fig. 6 is a perspective view of the lower end of the fixed tub of fig. 5 with the base removed.

Fig. 7 is an upper axial view of the bottom plate of another embodiment of the stationary tub depicting the location of a plurality of holding units.

FIG. 8 is a cross-sectional view of the stationary barrel of FIG. 7 taken along a set of linearly aligned retaining units in which the syringe is located and the base of FIG. 7 of the stationary barrel is attached to its body.

Fig. 9 is a detailed sectional view of the bottom of one of the holding units with the syringe disposed therein and the base attached to the stationary bucket.

Fig. 10 depicts a plot of the membrane layer profile in nanometers along the cartridge length (z) of the syringe sample/specimen before and after centrifugation (equivalent to 2 years of centrifugation).

Fig. 11 depicts a plot of initial film layer profile in nanometers along the cartridge length (z) of syringe samples 11-20.

Fig. 12 depicts a plot of initial film layer profile in nanometers along the cartridge length (z) of syringe samples 1-10.

Fig. 13 depicts a plot of the initial film profile (dimensionless thickness Ψ value of the silicone film) along the cartridge length (dimensionless form z from 0.0 to 1.0) of the syringe sample before centrifugation (t ═ 0).

Fig. 14 depicts a plot of model results of film layer contours (non-dimensional thickness Ψ values of the silicone film layer) along the cartridge length (z in non-dimensional form from 0.0 to 1.0) of the syringe sample during centrifugation (t ═ 0 and t ═ 1s equally spaced times (time scaled such that t ═ 1s corresponds to 2 years)). Note that the reference dimension of Ψ is the inner radius of the syringe, and thus Ψ is the layer thickness z at a particular location divided by the inner radius of the syringe cartridge.

Fig. 15 depicts a plot of predicted values of film layer profile (dimensionless thickness Ψ value of the silicone film layer) along the cartridge length of the syringe sample (dimensionless form of z from 0.0 to 1.0) comparing gravity drainage and centrifugal drainage (using low (T _ Fct ═ 0.0), medium (T _ Fct ═ 0.5) and high (T _ Fct ═ 1.0)).

Fig. 16 depicts a plot of film layer profile (dimensionless thickness of silicone film layer Ψ value) along the cartridge length of the syringe sample (dimensionless form of z from 0.0 to 1.0) comparing initial profile (T-0), centrifuge-expelled model results (using low (T _ Fct ═ 0.0), medium (T _ Fct ═ 0.5), and high (T _ Fct ═ 1.0)) and test results.

Fig. 17 depicts a plot of the average squared error between the gravity and centrifugal modeled results for all samples at three comparable times low (T _ Fct-0.0), medium (T _ Fct-0.5), and high (T _ Fct-1.0).

Fig. 18 depicts a plot of the average squared error between the model results and the centrifugation test results for all samples at three comparable times low (T _ Fct-0.0), medium (T _ Fct-0.5), and high (T _ Fct-1.0).

FIG. 19 is a flow chart indicating an exemplary testing method.

Detailed Description

For the purposes of promoting an understanding of the principles of the disclosure, reference will now be made to the embodiments illustrated in the drawings and specific language will be used to describe the same. It will nevertheless be understood that no limitation of the scope of the invention is thereby intended.

After the syringe has been siliconized, the syringe may be stored for a considerable length of time (where the syringe is typically stored with the needle end up and the flange end down, but aspects of the present disclosure are applicable to syringes stored with the flange end up and the needle end down, or any orientation in between). During this storage time, the initial distribution of silicone may change as the silicone drains from the top to the bottom under the force of gravity. Such variations can be appreciated if the long-term performance of the injector is to be controlled. The present disclosure describes a centrifugation method to accelerate the currently experienced methods for studying silicone discharge in syringes, which currently take years to complete. In one form, a method of accelerating aging of a siliconized syringe using a centrifuge is described. The basic predictive relationship of actual aging and centrifugal simulated aging is relevant. The use of centrifugation is useful for rapidly simulating injector functional changes after long-term storage in an empty state.

For example, an injector may be used alone as a drug delivery device, or may be used in combination with another device for setting and delivering a dose of a drug, such as pen injectors, infusion pumps, and auto injectors. The drug may be any type of drug that may be delivered by such a drug delivery device. The syringe may be provided empty or with medication. The term "drug" refers to one or more therapeutic agents, including but not limited to insulin, insulin analogs such as insulin lispro or insulin glargine, insulin derivatives, GLP-1 receptor agonists such as dolaglutide or liraglutide, glucagon analogs, glucagon derivatives, Gastric Inhibitory Polypeptide (GIP), GIP analogs, GIP derivatives, gastrin-modulating analogs, gastrin-modulating derivatives, therapeutic antibodies, and any therapeutic agent capable of being delivered by the above-described devices. The drug used in the device may be formulated with one or more excipients. The device is typically operated by a patient, caregiver or health care professional to deliver medication to a person in the manner described above.

An exemplary syringe 10 is shown in fig. 1. The syringe 10 comprises a syringe body 11, which syringe body 11 extends between an open proximal flange end 12 and a distal needle end 14 about a longitudinal axis LA. The plunger rod and piston assembly 15 may be mounted on the cylindrical cartridge 16 of the main body 11 through the open flanged end 12. The flanged end 12 is shown projecting radially outward beyond the outer diameter of the syringe cartridge 16. The piston 20 is sealably and slidably disposed along an inner surface 22 of the drug cartridge 16. The plunger rod shaft 25 is an elongated member coupled to the piston 20. The plunger rod shaft 25 projects proximally beyond the flange end 12 and is adapted to be pushed distally from an extended position (shown in fig. 1) to move the piston 20 distally within the cartridge 16 to dispense the medicament from a chamber 28 defined within the syringe cartridge between the piston 20 and the needle end 14. The cylindrical drug cartridge 16 extends from the flanged end 12 to a transition or shoulder 30 leading to a syringe needle hub 32 of reduced cross-sectional area less than the cylindrical drug cartridge 16. The flanged end 12 may protrude radially further outward than the cylindrical cartridge portion 16. The syringe body 11 may be made of glass, at least partially of glass, for example a glass cartridge with a plastic flange at its proximal end, or of a polymer suitable for syringe operation.

The syringe needle hub 32 may include a needle extending distally therefrom, or may be adapted to receive an attachable needle assembly (not shown). The distal end of the syringe cartridge 16 along the shoulder 32 includes a channel 38 in fluid communication with the chamber 28. An elongate needle cannula 35 (shown in phantom) includes a lumen extending therethrough between its proximal and distal ends 40, 42. The proximal end 40 of the needle cannula 35 is coupled to the distal needle end 14 of the syringe cartridge 16 through the passageway 38 to place the needle lumen in fluid communication with the chamber 28. In the illustrated example, the needle cannula 35 is securely attached to the syringe body 11 by use of an adhesive or other attachment means. In other examples, the needle may be removably attached to the syringe body 11, for example, by a needle attachment hub that is permanently attached to the needle cannula and frictionally attached around the needle hub 32 of the syringe. For the purposes of this disclosure, testing of the syringe may involve only the syringe body of the syringe 10, with the plunger and piston assembly 15 and needle 35 omitted, which is why these elements are shown in phantom.

One exemplary method of accelerating silicone discharge testing in syringes is to use centrifugation as a means of replacing gravity with a centrifugal force of high specific gravity. Centrifugal force induced silicone drainage may be closely related to gravity induced drainage, and centrifugal testing may be used in place of long-term gravity studies, possibly changing the study from years to hours. To this end, a mathematical model that allows ejection under both gravity and centrifugal forces was created and used to analyze a set of test data for a centrifugal-action syringe silicone ejection test. The model yields a quasi-linear first order Partial Differential Equation (PDE) that can be solved numerically.

A mathematical model for drop-in thin film flow ejection in a syringe cartridge was developed. The main assumptions involved in building this model are: (1) the membrane is thick enough to allow the use of continuous fluid dynamics. For example, for a Continuous flow hypothesis to be effective, a lower limit of a typical length scale for a liquid system may be given 1 μm (micrometer), see Hunter, S.C., 1976, "Mechanics of Continuous Media", Ellis Horwood Limited publishing, ISBN 85312-. In contrast, the silicone membrane in the syringe can be much smaller than 1 μm, thus, when comparing the model results with the experimental results, for example as shown in fig. 12, the effectiveness of extending the continuous medium method to such small membranes was determined. (2) The film thickness is small. This means that the velocity is small, resulting in a low reynolds number, and that the velocity gradient in the downward direction will be small. (3) The friction on the outer surface of the silicone layer is zero whether the syringe is empty or filled with liquid. In the former case, the silicone outer surface is in contact with air, while in the latter case the silicone layer is in contact with the liquid product material. (4) The effect of surface tension is negligible. The present disclosure uses the following terms in table 1:

TABLE 1

The model developed covers both gravity-induced and centrifugal force-induced discharge from a cylindrical syringe (e.g., syringe 10), as shown in fig. 2, with an initial dimension δ _o (z) the membrane 50 is disposed along the wall 16A of the syringe cartridge 16 (see Holland, F.A., 1973, "Fluid Flow for Chemical Engineers," Edward Arnold Ltd, ISBN 0-7131-.

Generally, the initial thickness of the membrane 50 will vary along the length of the syringe cartridge 16, but it is shown in fig. 2 as a constant initial thickness. Note that the z direction is considered as a downward direction in the same direction as the gravity and the centrifugal force. As shown in fig. 2, assuming that the syringe cartridge 16 surrounding the chamber 28 is ideally cylindrical, i.e. has a constant inner diameter D, this allows the use of cylindrical coordinates (z, r, θ). However, any coordinate convention may be used, such as cartesian coordinates. It is assumed that no dependent variable in the model is a function of angle (θ). At time 0 (zero), the membrane 50 will begin to drain downward under the force of gravity/centrifugal force. The velocity will develop in both the axial (z) and radial (r) directions. If the membrane 50 is assumed to be initially a thin membrane, the resulting velocity will be small and therefore the Reynolds number of the membrane will be small. Under these conditions, the flow "develops" very quickly, so the velocity in the r direction is assumed to be 0 (zero). Furthermore, in the equation for z-velocity, it is assumed that the inertial term, as well as any pressure gradient in the z-direction, can be ignored. The velocity in the z direction is then only a function of r and remains stable. Since there is only one velocity component u _z Therefore, the velocity is called u, becauseIn order not to obscure the velocity component to which it refers. Using these assumptions, the momentum balance in the z direction (from the Navier-Stokes equation) can be simplified to:

where μ is the dynamic viscosity of the liquid, ρ is the density of the liquid, and g is the gravity/centrifugal force. For gravity flow, g (z) is a constant g, but for centrifugation flow, g (z) is expressed as follows:

g(z)＝(r _C +z)ω ² (A.2)

wherein r is _C Is the radius of the centrifuge arm, ω is the angular velocity of the centrifuge in radians/second, and z represents the distance along the syringe from the end of the centrifuge arm.

Assuming that the speed u is a function of r only, equation (A.1) can be expressed in terms of ordinary derivatives rather than partial derivatives. This gives

Wherein

The equation for α (z) can be expressed as:

where β represents the effect of centrifugal force, where β -0 represents flow under gravity and β -1 represents flow under centrifugal force. The equations (a.3) and (a.4) are combined and the combined equations are integrated and the boundary conditions shown in equations (a.6) and (a.7) are applied. In the following, a clear correlation of the acceleration α with the direction z will be assumed, and therefore α (z) will be simply denoted as acceleration α.

Equation (a.3) can be integrated twice to produce a velocity expression as a function of density, acceleration, viscosity and layer thickness once the appropriate boundary conditions are applied. Here, the boundary conditions are:

wherein C is ₁ Is the integration constant. C can be found from one of the boundary conditions of the speed u ₁ I.e. the shear stress at the boundary of the membrane 50 is zero. Mathematically, this can be expressed as:

when in use

(equivalent to R ═ γ R) and γ ═ D-2 δ)/D,

(A.6)

where D is the inner diameter of the syringe cartridge 16 surrounding the chamber 28 and δ is the thickness of the membrane 50.

The second boundary condition is that there is no liquid slip at the inner surface of the glass syringe cartridge. This is given when

(corresponding to R ═ R), then u ═ 0 (a.7)

Integrating equation (a.3) and applying the boundary conditions in equations (a.6) and (a.7) yields:

now that the velocity profile as a function of r is known, the flow of the membrane 50 can be calculated when the thickness is δ. The flow Q in the z direction is given by:

substituting equation (a.8) into equation (a.9) yields:

the integral in equation (a.10) can be evaluated to yield:

wherein s (γ) is 1-4 γ ² +3γ ⁴ -4γ ⁴ ln(γ) (A.11)

Where γ <1, see equation (a.7), by definition of the dimensionless variable γ.

Now providing an equation for the flow Q, the unsteady evolution of the film thickness δ as a function of z can be estimated as a function of the film thickness δ. The unsteady mass balance on a slice (slice) between z and z + Δ z can be expressed as

Cumulative rate-inflow rate-outflow rate (a.12)

The volume in the slice, Δ V, is given by

Equation (A.13) can be simplified to

ΔV＝π(Dδ-δ ² )Δz (A.14)

Substituting equation (a.14) into equation (a.12) yields the following results.

Dividing both sides of equation (A.26) by Δ z and taking the limit as Δ z → 0 yields

Which can be simplified to

Due to the film thickness δ < < the inner diameter D of the syringe cartridge, equation (a.17) can be further simplified:

where Q is given by equation (A.11). It is now convenient to introduce another dimensionless psi, where:

so that

Equation (a.18) now becomes:

substituting Q in equation (a.11) into equation (a.20) yields:

wherein s (psi) is 1-4 (1-psi) ² +3(1-ψ) ⁴ -4(1-ψ) ⁴ ln(1-ψ)

(A.21)

Equation (a.21) can be simplified as:

in equation (A.22), ψ is a function of z and s (ψ) is a function of z. The common derivative in equation (A.22) can be found from equations (A.4) and (A.21)

The equation for s (ψ) and its derivatives can be simplified, because the film thickness δ < < inner diameter D, so ψ < < 1. The function ln (1-x) can be expanded to

Unfolding all terms in the equation for s (ψ) and its derivatives yields:

by using leading terms in the equations, these equations can be reduced to the following equations.

Substituting equation (A.22) and simplifying to obtain

The last step in the model is by using L _f (the length of the syringe from the end of the centrifuge center closest to the beginning of the film thickness measurement to the other end of the syringe, as shown in FIG. 4) and the total time span t of the model _f Z is normalized so that it is dimensionless in the z direction and time t. This produces the final form of the model equation:

now z and t are dimensionless variables of z and t, and the model runs from 0< ═ z < ═ 1 and 0< ═ t < ═ 1. The α (z) equation in dimensionless z form becomes:

and for the derivative, it becomes:

details involved in the derivation of model equation (1.0) are given in equations a.1 through a.33.

The last step in the model is to make z dimensionless in the z direction and time t by normalizing z with Lf (the length of the syringe from the end closest to the center of the centrifuge where the film thickness measurement begins to the other end of the syringe) and tf (the total time range of the model). Dimensionless z and t yield the final form of the mathematical model equation:

the model runs starting from 0< ═ z < ═ 1 and 0< ═ t < ═ 1. The equation for α (z) in dimensionless z form becomes:

and for the derivative, it becomes:

note that in equation (2.3), the derivative is relative to the original z, and not a dimensionless form of z. Thus, L _f Not present in equation (2.3). The model in equation (2.1) is in the form of the wave equation, where the wave velocity V _W Given by:

thus, the speed at which the silicone moves along the syringe cartridge and t _f Silicone density ρ, acceleration under gravity g, and r under centrifugal force _C Is in direct proportion. The wave speed is proportional to the square of the inner diameters D and ω. Wave velocity and L _f In inverse proportion. All of these variables are constant for a given configuration, and thus do not change the wave speed for an injector centrifuged to simulate aging. The variables that will change are z and

as z increases, the wave velocity increases, which reflects the longer radius of the centrifugal force. Driven by gravity or centrifugal force, the wave velocity follows

The square of (c) decreases. For this purpose, as the movement of the silicone proceeds,

the value tends to decrease.

The rate of descent being dependent on

Per se, therefore

Occurs at an earlier time than the start of the move.

The model also indicates how to scale the time so that the same effect is seen between gravity and centrifugal flow. Will t _f The value of (D) is expressed as t of gravity flow _fg And t of centrifugal action flow _fc ，t _fc And t _fg The ratio is given by:

in equation (2.5), the value of z must be chosen, keeping in mind 0<＝z<1. If the scaling in equation (2.5) is done with z set to 0, the centrifugal force over the entire silicone layer will be underestimated, and therefore the centrifugal action time, which is comparable to the gravitational action time, will be overestimated. If z is set to 1, the opposite occurs. If the dependence of the centrifugal force is linear in z, the optimum value of z to be used is likely to be close to 0.5. If the wave speed depends on the velocity of the wave in a linear manner

The optimum value used would be exactly 0.5. In the following examples, we shall examine the assertion that z-0.5 is better than z-0 or z-1. The parameter T _ Fct may be defined and used to rewrite equation (2.5) as:

t _ Fct-0.0 will be designated as Low (Low) state, T _ Fct-0.5 will be designated as medium (Mid) state, and T _ Fct-1.0 will be designated as High (High) state. These conditions were experienced at the end (T _ Fct ═ 1.0), middle (0.5) and flange (0.0) points to match the aging time to the corresponding points along the syringe.

Simulations carried out using the models shown here in equation (2.1) and equation (2.2) reproduce the experimental discharge in the injector under the effect of centrifugal force.

The model also shows that the time required for a given amount of silicone to drain can be scaled using equation (2.6) based on the first principle of fluid flow under gravity and centrifugal force. Simulations show that the most accurate silicone flow scaling is generated by a value of T _ Fct ═ 0.5 in the three conditions described above, low, medium and high. The matching point may be modified when an operator using the equation is selected. Matching different points may be preferable if different aspects of syringe behavior need to be understood. One example may be the use of a spring-driven auto-injector, where a thinner silicone layer at the tip may be of greater concern due to its potential for generating higher sliding forces or the use of increased injection times that may be observed from injection devices. In this case, T _ Fct is preferably chosen to be 0 to better match this point.

Since centrifugal force is a linear function of distance from the heart center, but acceleration due to gravity is virtually constant, a smaller centrifuge arm length to syringe cartridge length ratio will result in accurate scaling. The system described herein means that the ratio is at least 4: 1.

Note that one skilled in the art can apply other methods to develop models based on the key assumptions described above to achieve similar modeling results, while the principles are based on the key assumptions and methods outlined in the steps following model development. For example, a model can be developed using cartesian coordinates and assuming that the flow is planar rather than columnar due to the very thin membrane. In this case, equation (a.3) becomes:

if we assume that the glass surface corresponds to y ═ 0, then the two boundary conditions equivalent to (a.6) and (a.7) become:

at the point where y is equal to δ,

and where y is 0, u is 0(b.3)

Here, equations (b.2) and (b.3) correspond to (a.6) and (a.7) in the cylindrical coordinate model.

Integrating twice and applying the boundary conditions yields an equation equivalent to equation (a.8):

the equation equivalent to equation (a.10) becomes:

calculating the integral will yield an equivalent result to (a.11):

the volume slice described in (a.14) becomes:

ΔV＝πDδΔz (B.7)

this means that equation (a.18) is exactly the same here:

the dimensionless term Ψ has a small meaning because it assumes a planar geometry. Thus, the equivalent of equation (2.4) is shown below in the δ term rather than the Ψ term:

given the initially known silicone distribution δ (z, t) ₀ ) Equation (3.0) can be numerically integrated over time to obtain the relationship of δ (z, t).

Examples of the invention

In a preliminary test, a group of 20 syringes (having a configuration as described herein) was divided into two groups. The first set is designated samples 1 to 10 and the second set is designated samples 11 to 20. Centrifugation of samples 1 to 10 corresponded to 2 years of gravity flow, and centrifugation of samples 11 to 20 corresponded to 1 year of gravity flow. The layer film comprising silicone is measured before and after centrifugation using various test methods, such as an analytical method using an instrument to characterize the thickness distribution of the sprayed silicone oil layer in an empty prefilled syringe, also known as RapID. The measurement device reports the thickness at a z-distance of 0 to 49 millimeters, in 1 millimeter increments. At each z point, the device measures 9 points along the circumference. These 9 points were averaged to obtain the average silicone layer thickness at each z point.

Any centrifuge system may be used for testing. In one example, the centrifuge system 100 includes a Joean KR4-22 (S/N403100041) centrifuge, as shown in FIG. 3A. The centrifuge system 100 includes one or more stationary buckets configured to hold syringes. With additional reference to fig. 3B, the system 100 includes a rotor 120 that is rotatable relative to a system housing 122 about a shaft 123 extending about a rotational axis RA. The shaft 123 extends from and is coupled to a motor drive (not shown), such as an electric motor. In one example, the rotor 120 has a star configuration with a plurality of rotor arms 121 disposed radially spaced from one another by gaps 126 in which gaps 126 syringe retaining barrels (such as the syringe retaining barrels shown in fig. 5-6) are received. In one example, compartments 128 are formed in the housing in the gaps 126, respectively, wherein such compartments 128 are sized and shaped to receive a stationary tub. In fig. 4, the long arm length LR from the axis of rotation RA of the rotor arm 121 relative to the length Lf of the sample test syringe 10' is 4:1 (centrifuge rotor arm length/syringe cartridge length). Using a ratio of at least 4:1 can improve the fidelity of the silicone profile away from the match point. In one example, the centrifuge rotor 120 of the centrifuge system 100 may have a sufficient number of compartments to receive six buckets 125, but may include any number of buckets. Each compartment 128 may be sized and shaped to receive a stationary barrel, such as shown in fig. 5-6, to hold the syringe 10' in the correct orientation and position.

The operating characteristics of the rotor 120 of the centrifuge system 100, i.e., speed (whether constant or variable) or other characteristics, are controlled by a system controller 130, which system controller 130 is shown in phantom to indicate that it is housed within the system housing 122. The system controller 130 includes at least one processor 132 in electrical communication with an internal memory 134 (e.g., internal flash memory, on-board erasable programmable read-only memory (EEPROM), etc.) and a power source, such as a voltage source. The system controller 130 may be coupled to various operational sensors 136 integrated with the centrifuge and include control logic operable to perform the operations described herein to control the operation of the centrifuge, such as rotational speed and operating time. Processor 132 includes control logic operable to perform the operations described herein, including starting and stopping the centrifuge. Note that other control mechanisms may be selected as long as they control acceleration and time sufficiently to achieve the aforementioned simulation.

In one example, a centrifuge system comprises: a main body; a rotor rotatable relative to the body about a central axis by a motor; a compartment associated with the rotor; one or more syringes having a silicone membrane disposed in the compartment in a predetermined orientation, wherein a flange end of the syringe is disposed farther from the central axis than a needle end of the syringe; and a controller operably coupled to the motor, the controller configured to: the syringe centrifugation is activated at a predetermined G-rate for a centrifuge run time (tfc), where the simulated time is expressed as: tfg/tfc ═ ((r _ C + zL _ F) ω ^2)/g), where tfg is the gravity drainage time to be simulated, tfc is the centrifuge run time at speed ω in the centrifuge system with rotor arm length rc, match point z, injector length Lf, and g is the acceleration due to gravity. In one example, the ratio of the rotor arm length to the syringe length is greater than or equal to 4: 1. The predetermined G rate is constant or variable. The product zLf may be multiplied by a T fct factor, where the T fct factor is a value between 0 and 1. In one example, the T fct factor is 0.5. The system may include a cartridge holder configured to hold the syringe in a predetermined orientation, wherein the compartment is configured to receive the cartridge holder. The tub fixing device may include: a body defining a plurality of retention units, the retention units having a diameter sized to receive a cartridge of a syringe and sized not to receive a flanged end of the syringe; and a base plate defining a plurality of recesses arranged in coaxial alignment with respective retention units of the body, each recess having a diameter sized to be larger than a diameter of the retention unit and sized to receive a flanged end of a syringe and having a thickness sized to capture a thickness of the flanged end of the syringe, the base plate including an attachment feature for secure attachment to the lower end of the body.

An exemplary embodiment of a stationary bucket assembly 200 is shown in fig. 5-6. The securing assembly 200 includes a body 210 in the shape of a rectangular parallelepiped having generally body sides 212a-d defining a body length L, a body width W, and a body height H, respectively. The fixture body 210 may be solid or its sides may define a cavity 220. Fig. 5 shows an upper end perspective view of the upper end 225 of the tub body 210 in its upright position with the removable base 230 removed from the lower end 227. Fig. 6 shows the opposite lower end 227 of the tub body 210 in a lower end perspective view with the base 230 removed. The tub body 210 may include a plurality of retention units 235 extending at least partially between the upper end 225 and the lower end 227 of the body 210. The holding units 235 may be in any arrangement, including the 5 x 8 pattern shown. The holding unit 235 may be formed by machining an inner hole between the upper and lower ends or by a casting process. The shape of the holding unit may be similar to the shape of a conventional syringe, as shown in fig. 4 and 8. That is, as shown, the syringe shape includes an end or reduced cross-sectional area (or reduced cross-sectional area) associated with the needle end of the syringe, a middle linear area of constant cross-section associated with the syringe cartridge, and an enlarged cross-sectional area associated with the flange end of the syringe. The lower end 239 of the retention unit 235 is associated with the lower end 227 of the barrel body 210 and may define a conical tapered surface sized to receive the cross-sectional area of the flanged end 12 of the syringe. As shown, each unit 235 may be sized to receive a syringe cartridge without receiving a flanged end, as the flanged end is shown projecting radially outward beyond the syringe cartridge at diameter 12 b. The tapered surface is angled in a manner that accommodates the thickness of the flange end (shown as thickness 12a in fig. 1) so that the flange does not protrude beyond the plane defined by the lower end 227 of the body 210. The base 230 is sized to cover all of the holding units 235. As shown, the base 230 may be coupled to the tub body by mechanical fasteners (not shown) aligned with respective threaded

openings

231A, 231B in the base and tub body. As shown, the tub body 210 includes a handle 237 mounted on the upper end 225. In one example, the handle 237 has a U-shaped body with two attachment ends coupled to the upper end 225 and a portion extending between the two attachment ends in parallel and spaced apart relation to a plane defined by the upper end 225 of the main body 210, as shown.

The syringe is placed in the holding unit 235 with the flange end away from the center of the rotor. The placement of the syringe in the stationary barrel is shown in fig. 4. Fig. 7-9 illustrate another embodiment of the stationary tub assembly (now referred to as 200'). In fig. 7, an upper surface 251 of another example of a base, now referred to as base 230 ', which faces a lower end 227' of a tub body, now referred to as tub body 210 ', when attached, defines a plurality of recesses 252 arranged in alignment with corresponding retaining units formed in the tub body of the fixed tub assembly 200'. The attachment features have been omitted from the base 230' for clarity. In fig. 8, a cross-sectional view of the interface of the recess 252 with the end of the holding unit 235 that receives the syringe is shown. The cross-sectional area or Diameter (DR) of the recess may be greater than the cross-sectional area or Diameter (DH) of the cell. The combination of the Depth (DT) of the recess and the Diameter (DR) of the recess is dimensioned to allow the flange 12 'of the syringe 10' to fit snugly therein. To this end, with the bottom plate 230 ' removed, the syringe 10 ' is inserted into the unit 235 from the lower end 227 ' in a predetermined orientation such that the needle end 14 of the syringe 10 ' is closer to the upper end 225 ' of the tub body 210 ' than to the lower end 227 ' of the tub, as shown in fig. 9. The cross-sectional area or diameter of the syringe flange (diameter 12b in fig. 1) is greater than the cross-sectional area or Diameter (DH) of the unit, such that the flange protrudes outwardly from the lower end 227 'of the barrel body 210'. To this end, the lower surface 260 of the syringe flange 12 ' may engage with a corner edge 262, the corner edge 262 defining the intersection of the retention unit 235 with the lower end 227 ' of the main body 210 '. After all syringes are inserted (a portion of the unit may be left empty), a bottom plate 230' may be securely attached to the lower end of the barrel. For example, mechanical fasteners may be used between the lower end of the tub and the floor. The bottom plate 230 'may be configured to apply elevated pressure between the syringe flange 12' and the rim 262 to securely hold the syringe in a fixed position within the stationary barrel during operation of the centrifuge.

As shown in fig. 4, the stationary barrel 200 or 200 'is secured to the rotor arm 121 of the rotor 120 of the centrifuge system 100 such that the syringe flange end 12 or 12' of the syringe is furthest from the axis of rotation RA of the heart to allow discharge toward the flange end. Multiple buckets may be secured to respective arms of the system. The centrifuge system 100 is started at a predetermined G-rate (or radial acceleration) for a time period selected for the intended simulation. Centrifugation was terminated after the expected simulated period. After centrifugation, one or more injection function parameters of the syringe are evaluated.

One example of a test method (referred to as 1900) for accelerating the silicone discharge rate of an empty pre-filled siliconized syringe is shown in FIG. 19. The method may comprise one or more of the following steps: (a) a syringe including a silicone membrane is placed in a centrifuge rack of a centrifuge system in a predetermined orientation (step 1910). One preferred orientation corresponds to the intended storage orientation. For typical "needle up" storage, this orientation corresponds to an orientation in which the needle end is disposed away from the acceleration (or in other words, the syringe flange end is further from the central axis of the machine than the needle end). Other syringe orientations may be employed, as described herein. (b) The centrifuge of the centrifuge rack of the centrifuge system with the syringe is started at a predetermined G-rate for a desired simulated time (step 1920). (c) After the expected simulation time period has elapsed, centrifugation of the centrifuge rack with syringe is terminated (step 1930). (d) After the period of time has elapsed, one or more injection function parameters of the injector, such as properties related to the silicone layer, are evaluated (step 1940). In another example, the silicidation injector is a non-crosslinked silicidation injector. In another example, the elapsed time is represented as

Wherein t is _fg Is the gravity-action discharge time to be simulated, t _fc Is of arm length r _c Matching point z and syringe length L _F The centrifuge run time at speed ω, and g is the acceleration due to gravity. In other examples, the parameter comprises any one of release force, slip force, total silicone content, silicone layer profile, injection time from an injection device, or any combination thereof.

The evaluation in step 1940 may be done by filling (optionally air for evaluating syringe release force and plunger slip force) and inserting the syringe, then testing with appropriate fixtures and force displacement test stations to determine release force and slip force. A suitable description can be found in ISO 11040. The silicone content can be accomplished by any relevant analytical method, including gravimetrically weighing empty syringes before and after solvent extraction to remove silicone and drying to remove solvent. Alternatively, the solvent may also be collected and analyzed to determine the amount of extracted silicone. To determine the profile of the silicone layer, analytical methods can be used to characterize the sprayed silicone oil layer in the empty prefilled syringe, for example, see PDA J Pharm Sci technol.2018, 5 months-6 months; 72(3) 278-297.doi 10.5731/pdajpst.2017.007997. Epub.2018, 1 month and 17 days.

One of the benefits of this approach is to provide accelerated data for clinical trials. Another benefit is that a better, faster data set can be provided for drug archiving. As a result, the container packaging system or the lubrication profile may change. The test method provides for the use of centrifugation to simulate the long-term effects of gravity.

An exemplary test method, such as method 1900, is performed with centrifuge system 100. An example of data obtained by applying this method is shown in fig. 10, which shows the silicone front and back profile of sample 4 at 2 years of equivalent life, the thickness of the silicone layer in nanometers versus the distance in the z direction in millimeters. The first curve 1000 is the initial (pre-centrifugation) silicone profile, while the second curve 1010 is the post-centrifugation (post-centrifugation) silicone profile over a 2 year equivalent period. In the test configuration, the position z-0 is at the open end of the syringe, in which case the measurement is started there with RapID. Using RapID, the measurement range is from about 1mm inside the flange ("zero" on the graph in fig. 10) to 50mm inside the flange (point 49mm on the graph). Where the needle end is facing 50mm and the flange end is facing zero. The notation Ψ represents the thickness of the silicone layer at the selected point divided by the radius of the injector, using this convention as a convenient way to simplify the above equation to generalize the model. The syringe cartridge is 54.5mm long, but the measuring device (RapID) can only reach a position (at the needle end) where z is 49 mm. The designation of z in the test results is the opposite of that used in the model, where z-0 in the model represents the end of the test results where z is 49 mm. In fig. 10, the silicone flows in the negative z-direction. Since the syringe is stored with the needle side up (in this example), this means that the direction of the centrifugal force is the same as the direction of gravity.

The initial pre-silicone layer is shown for samples 11-20 in fig. 11 and for samples 1-10 in fig. 12, with the thickness of the silicone layer in nanometers versus the distance in the z-direction in millimeters. These two graphs show that for larger values of z (near the needle end), the variation between samples is small at graph area 1100 in fig. 11 and at graph area 1200 in fig. 12, respectively, while at z-0 (flange end), the variation between samples is larger at graph area 1110 in fig. 11 and at graph area 1210 in fig. 12, respectively. The initial silicone distribution data was used as input to a model that predicts the final distribution after centrifugation and after equivalent storage time under normal gravitational forces.

Parameter specification of model

Using the above geometric information, the centrifugal action time corresponding to the gravitational action fall time of 1 year and 2 years can be found based on the ratio of the centrifugal acceleration to the acceleration due to gravity. The results of the calculation of the centrifugation time are shown in Table 2.

TABLE 2

	T_Fct＝0.0		T_Fct＝0.5		T_Fct＝1.0
							Length of syringe (rc)	204.5	mm	204.5	mm	204.5	mm
Length of the cartridge	49	mm	49	mm	49	mm
							Inner diameter of cartridge	8.65	mm	8.65	mm	8.65	mm
RPM	3500	rev/min	3500	rev/min	3500	rev/min
							Simulation time
1	2	Year of year	2	Year of year	2	Year of year
							Simulation time
2	4	Year of year	4	Year of year	4	Year of year



Length of syringe (rc1)	0.2045	m	0.2045	m	0.2045	m
							Length of the cartridge	0.049	m	0.049	m	0.049	m
RPM	58.33	rev/s	58.33	rev/s	58.33	rev/s
							Omega	366.52	rad/s	366.52	rad/s	366.52	rad/s
Typical length	0.2045	m	0.229	m	0.2535	m

Simulation time of 1 year	63072000	s	63072000	s	63072000	s
							Simulation time of 2 years	126144000	s	126144000	s	126144000	s

							Acceleration of a vehicle	27471.77	m/s ²	30763.01	m/s ²	34054.25	m/s ²
G	9.81	m/s ²	9.81	m/s ²	9.81	m/s ²
							G equivalent	2800.38		3135.88		3471.38

							Required duration of centrifugation 1	22523	s	20113	s	18169	s
Required duration of centrifugation 2	45045	s	40226	s	36338	s

Required duration of centrifugation 1	6.26	hr	5.59	hr	5.05	hr
							Required duration of centrifugation 2	12.51	hr	11.17	hr	10.09	hr

The radius used for the centrifugal acceleration is (rC + T _ Fct × Lf). Three sets of calculations are shown in table 2. The first group assumes that z is 0(T _ Fct 0.0) as a representative value of z used for calculation. The results show that 6.26 hours of centrifugation should be used for 1 year and 12.51 hours for 2 years. If a value of T _ Fct ═ 0.5 is used as a representative point for centrifugal acceleration calculation, these times are 5.59 hours and 11.17 hours, respectively. Finally, if a value of T _ Fct ═ 1.0 is used as a representative point for centrifugal acceleration calculation, these times are 5.07 hours and 10.09 hours, respectively.

Results

The results of general centrifugation can be demonstrated using the methods described herein. The following categories may be used to determine and characterize the results, as shown in table 3.

TABLE 3

FIG. 13 shows the initial profile (Psi ) of the silicone layer along syringe sample 4 with the needle end up at 0 and the flange end at 1, with line 1300. Fig. 14 shows the modeling results (time scaling such that t 1s is equivalent to 2 years) between this initial profile (Psi) (at line 1400) at equal intervals between t 0 and the final profile (Psi) (at line 1410) of the silicone layer at t 1 s.

The results in fig. 14 show several features of the model: (a) the model tends to smooth the silicone layer profile. After 2 years, all kinks/kinks in the original profile disappeared. (b) The earlier time when the contour is larger than later has a greater effect on the contour. This can be seen by the fact that: the gap between successive contours in fig. 14 is smaller at a later time than at an earlier time. This is predicted earlier because the wave speed depends on the square of the silicone layer size. The dashed

ellipses

1420, 1430 in fig. 14 represent this difference.

For each sample, the following chart may be viewed. In fig. 15, predicted values of the dimensionless thickness ψ (Psi) of the centrifugally discharged silicone layer for the gravity action discharge (at line 1510) and the calculation of the equivalent centrifuging time using Low (Low) (T _ Fct ═ 0.0) (at line 1520), medium (Mid) (T _ Fct ═ 0.5) (at line 1540) and High (High) (T _ Fct ═ 1.0) (at line 1530) are shown. These graphs show that the general trend in the case of gravity discharge is reproduced by the case of centrifugal discharge. Thus, model prediction supports the use of centrifugation in a short time to simulate the effects of gravity ejection over a long time.

Fig. 16 compares the test results of the dimensionless thickness ψ of the silicone layer along the syringe centerline at the end of centrifugation (at line 1600) with model predictions of the dimensionless thickness ψ of the silicone layer using Low (Low) (T _ Fct ═ 0.0) (at line 1610), Mid (Mid) (T _ Fct ═ 0.5) (at line 1620) and High (High) (T _ Fct ═ 1.0) (at line 1630) calculations of the equivalent centrifugation time. The graph shows that the comparison between the model and the test results is good except for inaccuracies/errors in the initial region, since the measurement system cannot extend to the end, and there may be silicone in this region that will flow into the region measured at z-0, so it is expected that the test results will be higher than the results predicted by the model here.

The following sections focus on the results summarizing all samples. Fig. 17 shows the average squared error between the modeled results for gravity and centrifugation at three equivalent times, Low (T _ Fct ═ 0.0) (at line 1700), medium (Mid) (T _ Fct ═ 0.5) (at line 1710) and High (High) (T _ Fct ═ 1.0) (at line 1720). The graph shows that using the midpoint of the syringe to calculate a representative centrifugal force (to calculate an equivalent centrifugation time) is one of the first choices that matches the reduction in silicone content over time, among the three choices. For other devices or features, it may be more desirable to use other match points between 0 and 1 to evaluate other features, and the selected match point may also depend on the application.

Fig. 18 shows the mean squared error between the model prediction and the test results for all 20 samples. The following observations can be made from this graph in fig. 18. The model errors were consistent between the 1-10 sample set (two year simulation) and the 11-20 sample set (one year simulation). That is, all 1 year samples have approximately the same mean square error, and all 2 year samples have approximately the same mean square error. The model predicts that the test result matches for 2 years of samples 1-10 are significantly better than for 1 year of samples 11-20. This indicates that the model prediction will become better as the drain time is extended. This may be due to the fact that: more silicone is expelled over a longer period of time and the layer thickness changes less with time. The difference between the mean squared errors for different T _ Fct values (Low, Mid, High) is less than the variability between samples, so it is not possible to derive from this data which T _ Fct value is the best value for calculating the equivalent centrifugation time. The data in fig. 18 gives a better indication of this, as described herein. The agreement between model predictions and test results after 2 years was very good. As already discussed, the region close to z ═ 0 does not fit well because it is supplied by a silicone layer with z <0 that cannot be measured by the measuring device.

The discharge of the silicone layer in the syringe can be modeled using a centrifuge accelerated discharge and results reasonably consistent with the experiment, especially for longer times. In addition, the model shows that the predicted results using a centrifuge with a radius large enough to minimize the effect of acceleration variations along the syringe are similar to those obtained using an equivalent centrifuge action time to drain under gravity, it can be concluded that an acceleration test discharging silicone using a centrifuge running an equivalent drain time will reproduce the drain under gravity. Further, the results show that the optimal point for estimating the silicone discharge from the syringe over time matches the centrifugal force located at half the length of the syringe, while other matching points may be more suitable for the particular combination of syringe characteristics of interest (thickness of silicone layer, sliding force, etc.) and the particular application (e.g., manual pre-filled syringe, auto-injector, or bolus syringe).

To clarify its use and thereby apprise the public, the terms "< a >, < B >,. < N > or at least one of" < a >, < B >, < N >, or a combination thereof "or" < a >, < B >,. and/or < N > "are defined by the applicant in the broadest sense unless the applicant expressly claims to the contrary that, instead of any other implicit definition above or below, one or more elements selected from the group consisting of a, B,. and N are intended to be indicated. In other words, the term denotes any combination of one or more of the elements a, B,.. or N, including any element alone or in combination with one or more other elements, which may also include other elements not listed.

While various embodiments have been described, it will be apparent to those of ordinary skill in the art that many more embodiments and implementations are possible. Thus, the examples described herein are examples, rather than the only possible examples and implementations. Moreover, the advantages described above are not necessarily the only advantages, and it is not necessarily expected that every embodiment will achieve all of the described advantages.

Various aspects are described in the present disclosure, including but not limited to the following:

1. a test method for accelerating silicone discharge rate of a siliconized injector, comprising: placing a syringe comprising a silicone membrane into a centrifuge rack of a centrifuge system in a predetermined orientation, the syringe comprising a needle end and an opposing flange end, the predetermined orientation of the syringe comprising the flange end disposed farther from a central axis of the centrifuge system than the needle end or the needle end disposed farther from the central axis of the centrifuge system than the flange end; initiating centrifugation of a centrifuge rack of the centrifuge system with the syringe at a predetermined G-rate for a predetermined period of time; after the period of time has elapsed, ending centrifugation of the centrifugation rack with the syringe; and evaluating one or more injection function parameters of the injector after the period of time has elapsed.

2. The testing method of aspect 1, wherein the membrane of the syringe comprises a non-crosslinked silicone.

3. A test method according to any one of the preceding aspects, wherein the elapsed time is expressed as: (t) — (expected simulation time) (acceleration due to gravity) ]/[ (square of centrifugal action rotational speed) (distance from the center of the rotor hub to the matching point on the syringe cartridge) ].

4. A testing method according to any of the preceding aspects, wherein a ratio of a length of a rotor arm of the centrifuge system to a length of a cartridge of the syringe is greater than or equal to 4: 1.

5. The test method of any one of the preceding aspects, wherein one of the parameters comprises a release force.

6. A test method according to any preceding aspect, wherein one of the parameters comprises slip force.

7. A test method according to any one of the preceding aspects, wherein one of the parameters comprises silicone content.

8. A testing method according to any one of the preceding aspects, wherein one of the parameters comprises a silicone layer profile.

9. A test method according to any one of the preceding aspects, wherein one of the parameters comprises an injection time of the injector.

10. A test method according to any one of the preceding aspects, wherein the predetermined G-rate is constant.

11. A test method according to any preceding aspect, wherein the predetermined G-rate is variable.

12. A test method for accelerating silicone discharge rate of a siliconized injector, comprising: placing a syringe comprising a silicone membrane into a centrifuge rack of a centrifuge system in a predetermined orientation, the syringe comprising a needle end and an opposing flange end, the predetermined orientation of the syringe comprising the flange end disposed farther from a central axis of the centrifuge system than the needle end or the needle end disposed farther from the central axis of the centrifuge system than the flange end; starting the centrifugation of the centrifuge rack of the centrifuge system with the syringe at a predetermined G-rate for a predetermined period of time (fc), wherein the period of time (fc) is expressed as:

wherein t is _fg Is the gravity drainage time to be simulated, t _fc Is at a length r of the rotor arm _c Matching point z, syringe length L _F The centrifuge run time at a rotational speed ω in the centrifuge system of (a), and g is acceleration due to gravitational effects; and ending centrifugation of the centrifugation rack with the syringe after the period of time has elapsed.

13. The testing method of aspect 12, wherein a ratio of a length of a rotor arm of the centrifuge system to a length of a cartridge of the syringe is greater than or equal to 4: 1.

14. The test method of any one of aspects 12-13, wherein the predetermined G rate is constant.

15. The test method of any one of aspects 12-13, wherein the predetermined G-rate is variable.

16. The testing method of any of aspects 12-15, further comprising evaluating one or more injection function parameters of the injector after the period of time has elapsed.

17. The testing method of aspect 16, wherein one of the parameters comprises at least one of release force, slip force, silicone content, and silicone layer profile.

18. The testing method of aspect 16, wherein one of the parameters comprises an injection time of the injector, which may be a self-injecting injector device, also referred to as an auto-injector.

19. A syringe testing apparatus for a centrifuge system, the syringe having a cartridge with a cartridge diameter and a flange end diameter greater than the cartridge diameter, the apparatus comprising: a body defining a plurality of cells extending between upper and lower ends of the body, each cell having a diameter sized to receive a cartridge of the syringe but not a flange of the syringe; and a bottom plate defining a plurality of recesses, each recess arranged in coaxial alignment with a respective cell of the body, each recess having a diameter sized larger than the diameter of the cell and a depth sized to capture the thickness of the flange of the syringe, the bottom plate including an attachment feature for secure attachment to the lower end of the body.

20. The syringe testing apparatus of aspect 19, wherein each holding unit has a syringe-shaped configuration.

Claims

1. A test method for accelerating silicone ejection rate of a siliconized injector, comprising:

(a) placing a syringe comprising a silicone membrane into a centrifuge basket of a centrifuge system in a predetermined orientation, the syringe comprising a needle end and an opposing flange end, the predetermined orientation of the syringe comprising the flange end disposed further from a central axis of the centrifuge system than the needle end or the needle end disposed further from the central axis of the centrifuge system than the flange end;

(b) starting the centrifugation of the centrifuge rack of the centrifuge system with the syringe at a predetermined G-rate for a predetermined period of time t _fc ；

(c) After the predetermined period of time has elapsed, ending centrifugation of the centrifugation rack with the syringe; and

(d) evaluating one or more injection function parameters of the injector after the predetermined period of time has elapsed.

2. The testing method of claim 1, wherein the membrane of the syringe comprises a non-crosslinked silicone.

3. A test method according to any one of the preceding claims, wherein the predetermined period of time t is predetermined _fc Expressed as:

wherein t is _fg Is the gravity drainage time, t, to be simulated _fc Is the length r of the rotor arm from the central axis to the starting point of the silicone membrane of the injector _c Matching point z, syringe length L covered by the silicone layer measuring device _F And g is acceleration due to gravity.

4. Testing method according to claim 1 or 2, wherein the ratio of the long arm Length (LR) of the rotor arm of the centrifuge system to the length of the cartridge of the syringe is greater than or equal to 4: 1.

5. A test method according to claim 1 or 2, wherein the parameter comprises a release force.

6. A test method according to claim 1 or 2, wherein the parameter comprises slip force.

7. A test method according to claim 1 or 2, wherein the parameter comprises silicone content.

8. A test method according to claim 1 or 2, wherein the parameter comprises a silicone layer profile.

9. A test method according to claim 1 or 2, wherein the parameter comprises an injection time of the injector.

10. A test method according to claim 1 or 2, wherein the predetermined G-rate is constant.

11. A test method according to claim 1 or 2, wherein the predetermined G-rate is variable.

12. The method of testing of claim 1, wherein the syringe is placed into a syringe testing apparatus, the syringe comprising a cartridge having a cartridge diameter and a flanged end having a diameter greater than the cartridge diameter, wherein the apparatus comprises:

a body defining a plurality of retention units extending between upper and lower ends of the body, each retention unit having a diameter sized to receive a cartridge of the syringe but not a flange of the syringe; and

a bottom plate defining a plurality of recesses, each recess arranged in coaxial alignment with a respective retention unit of the body, each recess having a diameter sized larger than a diameter of the retention unit and a depth sized to capture a thickness of a flange of the syringe, the bottom plate including an attachment feature for secure attachment to a lower end of the body.

13. The testing method of claim 12, wherein each holding unit has a syringe-shaped configuration.

14. A test method for accelerating silicone ejection rate of a siliconized injector, comprising:

(b) starting the centrifugation of the centrifuge rack of the centrifuge system with the syringe at a predetermined G-rate for a predetermined period of time t _fc Wherein the predetermined period of time t is _fc Expressed as:

wherein t is _fg Is the gravity drainage time to be simulated, t _fc Is the length r of the rotor arm from the central axis to the starting point of the silicone membrane of the injector _c Matching point z, syringe length L covered by the silicone layer measuring device _F The centrifuge run time at a rotational speed ω in the centrifuge system of (a), and g is acceleration due to gravitational effects; and

(c) ending centrifugation of the centrifugation rack with the syringe after the predetermined period of time has elapsed.

15. The testing method of claim 14, wherein a ratio of a length of a rotor arm of the centrifuge system to a length of a cartridge of the syringe is greater than or equal to 4: 1.

16. A test method according to claim 14 or 15, wherein the predetermined G-rate is constant.

17. A test method according to claim 14 or 15, wherein the predetermined G-rate is variable.

18. A test method according to claim 14 or 15, further comprising assessing one or more injection function parameters of the injector after the predetermined period of time has elapsed.

19. The testing method of claim 18, wherein the parameters include at least one of release force, slip force, silicone content, and silicone layer profile.

20. The testing method of claim 18, wherein the parameter comprises an injection time.